Microtubules are dynamic copolymers of α and β tubulin sub units, which play a critical role in many cellular process, maintenance of cell shape, motility, cell signalling and serve to organize and segregate chromosomes during the mitosis (Jordan M A, Wilson L, Microtubules as a target for anticancer drugs, Nat. Rev. Cancer, 2004, (4), 253-265; Prasad V. Jallepalli & Christoph Lengauer Chromosome segregation and cancer: cutting through the mystery Nature Reviews Cancer, 1, 109-117). Chemical agents targeting the microtubules dynamics by the inhibition of tubulin protein have emerged as potential chemotherapeutic compounds for the treatment of various cancers. These agents are known to bind to different domain of the tubulin protein and prevent the polymerization or depolymerisation of the microtubules resulting in mitotic spindle arrest (Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGowan, A. T. Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle. Med. Res. Rev. 1998, 18, 259-296).
Colchicine (S1) and combretastatins (CA-4; S2) are well established natural agents that effectively bind at the colchicine site of tubulin and inhibit the polymerization resulting in the arrest of cell proliferation (McGowan A. T, Fox B. W, Structural and biochemical comparison of the anti-mitotic agents colchicines, combretastatin A4 and amphethinile, Anti-Cancer Drug Design, 1989, 3, 249). CA-4 is one of the preferred lead compounds in the development of new tubulin inhibitors because of its high potency and the limitation of low aqueous solubility. To overcome this, CA-4 based analogues such as CA4P, AVE8062 and AVE8063 have been developed and are undergoing clinical trials (Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. A. Medicinal chemistry of combretastatin A4: present and future directions. J. Med. Chem. 2006, 49, 3033-3044). Recently it has been reported that a new class of combretastatins such as (Z)-5-(3, 5-dimethoxystyryl)-2-methoxyaniline (S3) inhibits tubulin polymerization stronger than CA-4 by five folds. This new class binds at colchicine binding site and exhibit potent inhibition of cell proliferation against CA-4 resistant BMEC and HT-29 cell lines (Simoni D, Romagnoli R, Baruchello R, Rondanin R, Grisolia G, Eleopra M, Rizzi M, Tolomeo M, Giannini G, Alloatti D, Castorina M, Marcellini M, Pisano C, Novel A-ring and B-ring modified combretastatin A-4 (CA-4) analogues endowed with interesting cytotoxic activity, J. Med. Chem. 2008, 51, (19), 6211-6215).
More recently a report revealed that a series of phenylcinnamide derivatives (S4) exhibits significant activities against a number of tumor cell lines including multidrug resistant phenotype and it was also demonstrated that these compounds represent a new class of inhibitors of tubulin polymerization (Benjamin J. Leslie, Clinton R. Holaday, Tran Nguyen, and Paul J. Hergenrother, Phenylcinnamides as Novel Antimitotic Agents, J. Med. Chem. 2010, 53, 3964-3972). In continuation of these efforts and our interest in the structural modifications of the combretastatin A4, we describe herein an efficient access to the construction of some new N-(3,4,5-trimethoxystyryl)aryl)cinnamamides incorporating the phenylcinnamide and CA-4 pharmacophoric structures with improved cytotoxicity.
